Biomaterials engineering and biotechnology have advanced significantly towards probiotic encapsulation with encouraging results in assuring sufficient bioactivity. However, some major challenges remain to be addressed, and these include maintaining stability in different compartments of the gastrointestinal tract (GIT), favoring adhesion only at the site of action, and increasing residence times. An alternative to addressing such challenges is to manufacture encapsulates with stimuli-responsive polymers, such that controlled release is achievable by incorporating moieties that respond to chemical and physical stimuli present along the GIT. This review highlights, therefore, such emerging delivery matrices going from a comprehensive description of addressable stimuli in each GIT compartment to novel synthesis and functionalization techniques to currently employed materials used for probiotic’s encapsulation and achieving multi-modal delivery and multi-stimuli responses. Next, we explored the routes for encapsulates design to enhance their performance in terms of degradation kinetics, adsorption, and mucus and gut microbiome interactions. Finally, we present the clinical perspectives of implementing novel probiotics and the challenges to assure scalability and cost-effectiveness, prerequisites for an eventual niche market penetration.